AUBAGIO

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AUBAGIO

Classes

MS Agents
Pyrimidine Synthesis Inhibitors

Administration

Hazardous Drugs Classification
NIOSH 2016 List: Group 2
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.

Oral Administration Oral Solid Formulations

May be taken with or without food.

Adverse Reactions
Severe

renal failure (unspecified) / Delayed / 0-0.8
hepatotoxicity / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
hyperkalemia / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
pulmonary fibrosis / Delayed / Incidence not known
eosinophilic pneumonia / Delayed / Incidence not known
fetal death / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known

Moderate

myasthenia / Delayed / 37.9-42.0
cystitis / Delayed / 7.3-23.5
hyperreflexia / Delayed / 21.2-23.5
elevated hepatic enzymes / Delayed / 5.8-22.7
hypophosphatemia / Delayed / 4.0-18.0
lymphopenia / Delayed / 10.0-12.0
neutropenia / Delayed / 4.0-6.0
hypertension / Early / 3.1-4.3
peripheral neuropathy / Delayed / 1.4-1.9
hyperbilirubinemia / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
immunosuppression / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
psoriasis / Delayed / Incidence not known
hyperuricemia / Delayed / Incidence not known
colitis / Delayed / Incidence not known
pneumonitis / Delayed / Incidence not known
dyspnea / Early / Incidence not known

Mild

infection / Delayed / 1.2-53.0
pharyngitis / Delayed / 21.0-53.0
hypoesthesia / Delayed / 48.1-50.0
fatigue / Early / 10.0-48.5
back pain / Delayed / 8.0-36.4
influenza / Delayed / 9.2-34.8
insomnia / Early / 9.0-34.6
dizziness / Early / 21.2-22.2
rash / Early / 16.7-22.2
headache / Early / 16.0-18.0
diarrhea / Early / 13.0-14.0
alopecia / Delayed / 10.0-13.0
nausea / Early / 8.0-11.0
paresthesias / Delayed / 8.0-9.0
arthralgia / Delayed / 6.0-8.0
pruritus / Rapid / 2.8-3.5
urticaria / Rapid / 0.8-1.1
carpal tunnel syndrome / Delayed / Incidence not known
abdominal pain / Early / Incidence not known
dyspepsia / Early / Incidence not known

Boxed Warning
Hepatic disease, hepatitis, hepatotoxicity, jaundice

Teriflunomide is contraindicated for use in patients with severe hepatic disease, as these patients may be at risk for further hepatic injury or development of elevated serum transaminases. Clinically significant and potentially life-threatening hepatotoxicity, including acute liver failure requiring transplant, has been reported in patients treated with teriflunomide during postmarketing experience. Patients with pre-existing acute or chronic hepatic impairment, such as hepatitis, jaundice, or those with serum ALT concentrations more than 2 times the upper level of normal (ULN) should usually not be treated with teriflunomide. Baseline liver function tests (LFTs) including serum transaminase and bilirubin concentrations should be measured within the 6 months before starting treatment. Monitor ALT concentrations at least monthly for 6 months after therapy initiation; additional monitoring may be necessary when teriflunomide is given with other hepatotoxic drugs. ALT and bilirubin monitoring should occur in patients presenting with unexplained potential symptoms of liver dysfunction including nausea, vomiting, fatigue, anorexia, or jaundice with or without dark urine. Consider drug discontinuation with serum transaminase increases more than 3 times the ULN. If liver injury is suspected, discontinue and begin an accelerated elimination procedure. Monitor weekly LFTs until normalization. If teriflunomide-induced liver injury is not suspected, therapy may be resumed.

Intrauterine fetal death, pregnancy

Teriflunomide is contraindicated for use during pregnancy. Animal studies indicate that teriflunomide may cause major birth defects and/or intrauterine fetal death during human pregnancy. Prospectively collected human data (from pregnancy registries, clinical trials, pharmacovigilance cases, and published literature) of more than 150 pregnancies exposed to teriflunomide and more than 300 pregnancies exposed to leflunomide do not indicate increased birth defects or miscarriage with inadvertent teriflunomide exposure in the early first trimester followed by an accelerated elimination procedure; however, data are too limited to be conclusive. There are no data about exposures later in the first trimester and beyond. In animal reproduction studies, high incidences of fetal malformations (primarily craniofacial, and axial and appendicular skeletal defects) and embryolethality were reported at plasma exposures (AUC) lower than that at the maximum human recommended dose of 14 mg/day. No well-controlled trials in humans are available. Women who wish to become pregnant should discontinue teriflunomide and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL); the patient should use effective contraception until it is verified that the plasma concentration has been lowered to this level. Human plasma concentrations of teriflunomide less than 0.02 mg/L are expected to have minimal risk to the fetus. The patient should be counseled to immediately contact their health care provider if pregnancy is suspected (e.g., a delay in menses) during treatment or anytime within the 2 years after discontinuing the drug, since teriflunomide may stay in the blood for up to 2 years following the last dose. Perform a pregnancy test if pregnancy is suspected. An accelerated teriflunomide elimination procedure should be used to rapidly lower teriflunomide concentration, which may decrease risk to the fetus. Refer the patient to an obstetrician or gynecologist, preferably experienced in reproductive toxicity, for further evaluation and management. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to terflunomide; information about the registry can be obtained at mothertobaby.org/ongoing-study/aubagio or by calling 1-800-745-4447, option 2 or 1-877-311-8972.[51794] [61642]

Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

All patients, both male and female, should be advised of the reproductive risk for teriflunomide. Teriflunomide may increase the risk of major birth defects, and it is contraindicated for use in females of reproductive potential not using effective contraception. A woman of reproductive potential must not begin treatment with teriflunomide until pregnancy is ruled out; perform pregnancy testing prior to treatment initiation. Risks associated with fetal exposure to teriflunomide during pregnancy should be discussed. An accelerated drug elimination procedure is recommended in all women of reproductive age who discontinue teriflunomide. Women receiving teriflunomide who wish to become pregnant must discontinue the drug and undergo an accelerated drug elimination procedure, which includes verification that the plasma concentration of teriflunomide is less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L are expected to have minimal risk to the fetus. Contraceptives should be continued during an accelerated drug elimination procedure in all females of reproductive age until it is verified that the plasma concentration of teriflunomide is less than 0.02 mg/L (0.02 mcg/mL). Contraception requirements have also been advised for males. Teriflunomide is detected in human semen; studies evaluating male-induced fetal risk are not available. Male-mediated teratogenicity is a potential concern; male patients should use adequate contraception, and males wishing to father a child should discontinue the drug and undergo an accelerated elimination procedure or wait until verification that the plasma concentration of teriflunomide is less than 0.02 mg/L (0.02 mcg/mL). Advise all patients that teriflunomide may stay in the blood for up to 2 years after the last dose and that an accelerated elimination procedure may be used if needed. Patients should be counseled to immediately contact their health care provider if pregnancy is suspected. If a pregnancy is confirmed in a treated female, an accelerated teriflunomide elimination procedure may be considered to rapidly lower the teriflunomide concentration, which may decrease risk to the fetus.[51794] It is not clear if teriflunomide affects male fertility. Oral administration of teriflunomide (0, 1, 3, 10 mg/kg/day) to male rats prior to and during mating (to untreated females) resulted in no adverse effects on fertility; however, a reduced epididymal sperm count was observed at the mid and high doses tested. The no-effect dose for reproductive toxicity in male rats (1 mg/kg) is less than the MRHD on a BSA basis.[51794]

Common Brand Names

AUBAGIO

Dea Class

Rx

Description

Oral pyrimidine synthesis inhibitor; an active metabolite of leflunomide
Used in adults with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease
Boxed warnings regarding risk for hepatotoxicity and for teratogenicity

Dosage And Indications
For the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. Oral dosage Adults

7 mg or 14 mg PO once daily.

Dosing Considerations
Hepatic Impairment

Teriflunomide is contraindicated in patients with severe hepatic impairment. No dosage adjustment is needed in patients with mild or moderate hepatic impairment.

Renal Impairment

No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment.

Drug Interactions

Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Zidovudine, ZDV should be used cautiously with other drugs that can cause bone marrow suppression including teriflunomide because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage or discontinuation of zidovudine may be warranted. Teriflunomide, an organic anion transporter OAT3 renal updake inhibitor, may cause elevated concentrations of zidovudine, an OAT3 substrate.
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Acetaminophen; Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Acetaminophen; Caffeine; Dihydrocodeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Acetaminophen; Caffeine; Pyrilamine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Alemtuzumab: (Major) Concomitant use of teriflunomide with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
Alogliptin; Pioglitazone: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as pioglitazone. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
Alosetron: (Moderate) Use caution when administering teriflunomide and alosetron concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as alosetron, may decrease alosetron exposure and lead to a reduction in efficacy.
Alpelisib: (Major) Avoid coadministration of alpelisib with teriflunomide due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and teriflunomide is a BCRP inhibitor.
Amlodipine; Atorvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Anagrelide: (Moderate) Use caution when administering teriflunomide and anagrelide concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as anagrelide, may decrease anagrelide exposure and lead to a reduction in efficacy. Monitor platelet counts.
Aspirin, ASA; Butalbital; Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Aspirin, ASA; Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Atogepant: (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily for episodic migraine or 30 mg PO once daily for chronic migraine if coadministered with teriflunomide. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of OATP1B1 and OATP1B3 and teriflunomide is an OATP inhibitor. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration.
Atorvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Atorvastatin; Ezetimibe: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Baricitinib: (Moderate) Monitor for increased baricitinib effects if administered with teriflunomide as baricitinib exposure may increase; a baricitinib dose reduction may be necessary. Baricitinib is an OAT3 substrate; teriflunomide is an OAT3 inhibitor.
Bendamustine: (Major) Consider the use of an alternative therapy if teriflunomide treatment is needed in patients receiving bendamustine. Teriflunomide may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and teriflunomide is a CYP1A2 inducer.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking teriflunomide. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a BCRP substrate and teriflunomide is a BCRP inhibitor. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%.
Brincidofovir: (Moderate) Postpone the administration of teriflunomide for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and teriflunomide is necessary. Brincidofovir is an OATP1B1/3 substrate and teriflunomide is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
Bupivacaine; Lidocaine: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to lidocaine, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, lidocaine doses may need adjustment if teriflunomide treatment is discontinued.
Butalbital; Acetaminophen; Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Butalbital; Acetaminophen; Caffeine; Codeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Butalbital; Aspirin; Caffeine; Codeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Caffeine; Sodium Benzoate: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Cefaclor: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with cefaclor, a substrate of OAT3, may increase cefaclor plasma concentrations. Monitor for increased adverse effects from cefaclor, such as diarrhea, nausea, or abdominal pain. Adjust the dose of cefaclor as necessary and clinically appropriate.
Charcoal: (Major) Activated charcoal can bind with teriflunomide and enhance its clearance from the systemic circulation via intestinal trapping. Because teriflunomide has a prolonged half-life, staggering the administration times of each agent will not prevent this drug interaction. After 11 days of activated charcoal administration, teriflunomide concentrations are reduced by approximately 98%. Activated charcoal is used to facilitate teriflunomide elmination from the body when clinically necessary.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cholestyramine: (Major) Cholestyramine can bind with teriflunomide and enhance its clearance from the systemic circulation via intestinal trapping. Because teriflunomide has a prolonged half-life, staggering the administration times of each agent will not prevent this drug interaction. After 11 days of cholestyramine administration, teriflunomide concentrations are reduced by approximately 98%. Cholestyramine is used to facilitate teriflunomide elmination from the body when clinically necessary.
Cimetidine: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with cimetidine, a substrate of OAT3, may increase cimetidine plasma concentrations. Monitor for increased adverse effects from cimetidine, such as dose-related elevations in hepatic enzymes. Adjust the dose of cimetidine as necessary and clinically appropriate.
Ciprofloxacin: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with ciprofloxacin, a substrate of OAT3, may increase ciprofloxacin plasma concentrations. Monitor for increased adverse effects from ciprofloxacin, such as nausea, vomiting, diarrhea, or abdominal pain. Adjust the dose of ciprofloxacin as necessary and clinically appropriate.
Clofarabine: (Moderate) Concomitant use of clofarabine, a substrate of OAT1 and OAT3, and teriflunomide, an inhibitor of OAT protein (OATP), may result in increased clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g., hand and foot syndrome, rash, pruritus) in patients also receiving OATP inhibitors.
Clozapine: (Moderate) Caution is advisable during concurrent use of teriflunomide with clozapine. Teriflunomide induces CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Patients receiving clozapine in combination with a CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions and consider reducing the clozapine dose if necessary.
Cycloserine: (Moderate) In vitro studies indicate that teriflunomide is a substrate of ABCG2 (breast cancer resistance protein, BCRP). Drugs that are inhibitors of BCRP, such as cyclosporine, may cause increases in teriflunomide plasma concentrations. Monitor patients for adverse effects, including symptoms serious liver injury and immunosuppression.
Daprodustat: (Major) Reduce the initial daprodustat dose by half during concomitant use of teriflunomide unless the daprodustat dose is already 1 mg. Monitor hemoglobin and further adjust the daprodustat dose as appropriate. Concomitant use may increase daprodustat exposure and the risk for daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and teriflunomide is a moderate CYP2C8 inhibitor. Concomitant use with a moderate CYP2C8 inhibitor is expected to increase daprodustat overall exposure by approximately 4-fold.
Desogestrel; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Dichlorphenamide: (Moderate) Monitor for increased toxicity of dichlorphenamide, including hypokalemia and hyperchloremic metabolic acidosis, if teriflunomide and dichlorphenamide are coadministered. Dichlorphenamide is a substrate for OAT3. Teriflunomide may increase exposure to dichlorphenamide through OAT3 inhibition. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
Dienogest; Estradiol valerate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Diphenhydramine; Naproxen: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as naproxen. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects, including additive hepatotoxicity.
Drospirenone: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Drospirenone; Estetrol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Drospirenone; Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Drospirenone; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Duloxetine: (Moderate) Use caution when administering teriflunomide and duloxetine concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as duloxetine, may decrease duloxetine exposure and lead to a reduction in efficacy.
Elagolix: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as teriflunomide is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Teriflunomide inhibits OATP1B1 in vivo and is expected to increase concentrations of drugs that are substrates for OATP1B1. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as teriflunomide is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Teriflunomide inhibits OATP1B1 in vivo and is expected to increase concentrations of drugs that are substrates for OATP1B1. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density. (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of grazoprevir with teriflunomide is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Grazoprevir is a substrate of the organic anion-transporting peptide (OATP1B1/1B3); teriflunomide is an in vitro inhibitor of OATP.
Eltrombopag: (Moderate) In vitro studies indicate that teriflunomide is a substrate of ABCG2 (breast cancer resistance protein, BCRP). Drugs that are inhibitors of BCRP, such as eltrombopag, may cause increases in teriflunomide plasma concentrations. Monitor patients for adverse effects, including symptoms serious liver injury and immunosuppression.
Eluxadoline: (Major) When administered concurrently with teriflunomide, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); teriflunomide is an in vitro inhibitor of OATP.
Ergotamine; Caffeine: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Estradiol; Levonorgestrel: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Estradiol; Norethindrone: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Estradiol; Norgestimate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Ethinyl Estradiol; Norelgestromin: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Ethinyl Estradiol; Norgestrel: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Etonogestrel; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Ezetimibe; Simvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Fluvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Furosemide: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with furosemide, a substrate of OAT3, may increase furosemide plasma concentrations. Monitor for increased adverse effects from furosemide, such as excessive fluid loss or hypotension.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and teriflunomide as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of organic anion transporting polypeptide (OATP) 1B1/3 and breast cancer resistance protein (BCRP); teriflunomide is an inhibitor of these drug transporters. (Moderate) Caution is advised with the coadministration of pibrentasvir and teriflunomide as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of breast cancer resistance protein (BCRP); teriflunomide is an inhibitor of BCRP.
HMG-CoA reductase inhibitors: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Intranasal Influenza Vaccine: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Concurrent use of teriflunomide, an inhibitor of the hepatic uptake organic anion transporting polypeptides OATP1B1/1B3, with rifampin, an OATP substrate, may increase exposure to rifampin. Consider reducing the dosage of rifampin as necessary and clinically appropriate, and monitor patients closely. Additive hepatotoxicity or hematologic toxicity may occur. The potential for additive adverse effects should also be considered when such medications would be prescribed after teriflunomide administration has ceased, if the patient has not received the teriflunomide elimination procedure.
Isoniazid, INH; Rifampin: (Moderate) Concurrent use of teriflunomide, an inhibitor of the hepatic uptake organic anion transporting polypeptides OATP1B1/1B3, with rifampin, an OATP substrate, may increase exposure to rifampin. Consider reducing the dosage of rifampin as necessary and clinically appropriate, and monitor patients closely. Additive hepatotoxicity or hematologic toxicity may occur. The potential for additive adverse effects should also be considered when such medications would be prescribed after teriflunomide administration has ceased, if the patient has not received the teriflunomide elimination procedure.
Ketoprofen: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with ketoprofen, a substrate of OAT3, may increase ketoprofen plasma concentrations. Monitor for increased adverse effects from ketoprofen, such as nausea, vomiting, diarrhea, or decreased urine output. Adjust the ketoprofen dose as necessary and clinically appropriate.
Lamivudine, 3TC; Zidovudine, ZDV: (Major) Zidovudine, ZDV should be used cautiously with other drugs that can cause bone marrow suppression including teriflunomide because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage or discontinuation of zidovudine may be warranted. Teriflunomide, an organic anion transporter OAT3 renal updake inhibitor, may cause elevated concentrations of zidovudine, an OAT3 substrate.
Leflunomide: (Contraindicated) Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Leflunomide treatment is contraindicated in those patients currently receiving teriflunomide treatment. Duplicate treatment can lead to toxicity, including hepatic toxicity, bone marrow suppression, and infection risks. Overdose has caused diarrhea, abdominal pain, leukopenia, anemia, and elevated liver function tests.
Letermovir: (Moderate) Closely monitor for letermovir-related adverse events (i.e., tachycardia, atrial fibrillation, and gastrointestinal events) if administered with teriflunomide, as use of these drugs together may result in elevated letermovir plasma concentration. Letermovir is a substrate of the organic anion-transporting polypeptides (OATP1B1/3); teriflunomide is an inhibitor of OATP1B1/3.
Leuprolide; Norethindrone: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Levonorgestrel: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Lidocaine: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to lidocaine, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, lidocaine doses may need adjustment if teriflunomide treatment is discontinued.
Lidocaine; Epinephrine: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to lidocaine, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, lidocaine doses may need adjustment if teriflunomide treatment is discontinued.
Lidocaine; Prilocaine: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to lidocaine, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, lidocaine doses may need adjustment if teriflunomide treatment is discontinued.
Live Vaccines: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Lovastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Maraviroc: (Moderate) Use caution and closely monitor for increased adverse effects during concurrent administration of maraviroc and teriflunomide as increased maraviroc concentrations may occur. Maraviroc is a substrate of organic anion-transporting polypeptide (OATP1B1); teriflunomide is an inhibitor of OATP1B1. The effects of this transporter on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Measles/Mumps/Rubella Vaccines, MMR: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Metformin; Repaglinide: (Moderate) Closely monitor for hypoglycemia and for repaglinide-induced side effects when these drugs are used together. In some patients, a dosage reduction of repaglinide may be required. In vivo data suggest that teriflunomide is an inhibitor of CYP2C8, as increases in Cmax and AUC were observed following concurrent use of repaglinide, a CYP2C8 substrate. Repaglinide Cmax and AUC increased 1.7- and 2.4-fold, respectively, following a single dose of repaglinide 0.25 mg with repeated dosing of teriflunomide.
Metformin; Rosiglitazone: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as rosiglitazone. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
Methotrexate: (Major) Teriflunomide is an inhibitor of the hepatic uptake transporter organic anion transporting polypeptide OATP1B1 and the renal uptake organic anion transporter OAT3, while methotrexate is a substrate of both of these transporters. Concomitant use may produce greater potential for hepatotoxicity. The potential for hepatotoxicity should also be considered when such medications would be prescribed after teriflunomide administration has ceased, if the patient has not received the teriflunomide elimination procedure.
Mexiletine: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to mexiletine, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, mexiletine doses may need adjustment if teriflunomide treatment is discontinued.
Mitoxantrone: (Moderate) Concurrent use of teriflunomide, an inhibitor of the breast cancer resistance protein (BCRP), with mitoxantrone, a substrate of BCRP, may increase exposure to mitoxantrone. Consider reducing the dosage of mitoxantrone as necessary and clinically appropriate, and monitor patients closely. Additive hepatotoxicity or hematologic toxicity may occur. The potential for additive effects should also be considered when such medications would be prescribed after teriflunomide administration has ceased, if the patient has not received the teriflunomide elimination procedure.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with teriflunomide is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP2C8 substrate and teriflunomide is a moderate CYP2C8 inhibitor. In vitro, the metabolism of paclitaxel to 6-alpha-hydroxypaclitaxel was inhibited by another inhibitor of CYP2C8.
Naproxen: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as naproxen. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects, including additive hepatotoxicity.
Naproxen; Esomeprazole: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as naproxen. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects, including additive hepatotoxicity.
Naproxen; Pseudoephedrine: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as naproxen. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects, including additive hepatotoxicity.
Nateglinide: (Moderate) Closely monitor for hypoglycemia and for nateglinide-induced side effects when these drugs are used together. In some patients, a dosage reduction of nateglinide may be required. Concurrent use of teriflunomide, an inhibitor of the organic anion transporting polypeptides OATP1B1/1B3, may increase exposure to nateglinide, an OATP substrate. Consider reducing the dosage of nateglinide as necessary and clinically appropriate. Monitor patients for increases in adverse effects, which may include hypoglycemia.
Niacin; Simvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Norethindrone: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Norethindrone; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Norgestimate; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Norgestrel: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Ocrelizumab: (Moderate) Ocrelizumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis. Concomitant use of ocrelizumab with any of these therapies may increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects such as teriflunomide. The median half-life of teriflunomide is 18 to 19 days, and teriflunomide may remain in plasma for up to 2 years after discontinuation.
Ofatumumab: (Moderate) Concomitant use of ofatumumab with teriflunomide may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as teriflunomide. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients. The median half-life of teriflunomide is 18 to 19 days, and teriflunomide may remain in plasma for up to 2 years following discontinuation.
Oral Contraceptives: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Paclitaxel: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as paclitaxel. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
Penicillin G Benzathine: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with penicillin G, a substrate of OAT3, may increase penicillin G plasma concentrations. Monitor for increased adverse effects from penicillin G, such as nausea, vomiting, diarrhea, or seizures. Adjust the dose of penicillin G as necessary and clinically appropriate.
Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with penicillin G, a substrate of OAT3, may increase penicillin G plasma concentrations. Monitor for increased adverse effects from penicillin G, such as nausea, vomiting, diarrhea, or seizures. Adjust the dose of penicillin G as necessary and clinically appropriate.
Penicillin G Procaine: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with penicillin G, a substrate of OAT3, may increase penicillin G plasma concentrations. Monitor for increased adverse effects from penicillin G, such as nausea, vomiting, diarrhea, or seizures. Adjust the dose of penicillin G as necessary and clinically appropriate.
Penicillin G: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with penicillin G, a substrate of OAT3, may increase penicillin G plasma concentrations. Monitor for increased adverse effects from penicillin G, such as nausea, vomiting, diarrhea, or seizures. Adjust the dose of penicillin G as necessary and clinically appropriate.
Pioglitazone: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as pioglitazone. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
Pioglitazone; Glimepiride: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as pioglitazone. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
Pioglitazone; Metformin: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as pioglitazone. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
Pitavastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Pravastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Propafenone: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to propafenone, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, propafenone doses may need adjustment if teriflunomide treatment is discontinued.
Quinine: (Moderate) Use caution when administering teriflunomide and quinine concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2 and an inhibitor of CYP2C8. Coadministration of teriflunomide with CYP1A2 and CYP2C8 substrates, such as quinine, may lead to increases in adverse effects or possible efficacy reduction.
Rasagiline: (Moderate) Use caution when administering teriflunomide with rasagiline. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as rasagiline, may decrease rasagiline exposure and lead to efficacy reduction. If teriflunomide is discontinued in a patient taking either rasagiline, serum concentrations may increase. Monitor patients for increases in adverse effects, such as dyskinesia, hallucinations, or nausea. Dose adjustments may be required.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Repaglinide: (Moderate) Closely monitor for hypoglycemia and for repaglinide-induced side effects when these drugs are used together. In some patients, a dosage reduction of repaglinide may be required. In vivo data suggest that teriflunomide is an inhibitor of CYP2C8, as increases in Cmax and AUC were observed following concurrent use of repaglinide, a CYP2C8 substrate. Repaglinide Cmax and AUC increased 1.7- and 2.4-fold, respectively, following a single dose of repaglinide 0.25 mg with repeated dosing of teriflunomide.
Revefenacin: (Major) Coadministration of revefenacin is not recommended with teriflunomide because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; teriflunomide is an inhibitor of OATP1B1 and OATP1B3.
Rifampin: (Moderate) Concurrent use of teriflunomide, an inhibitor of the hepatic uptake organic anion transporting polypeptides OATP1B1/1B3, with rifampin, an OATP substrate, may increase exposure to rifampin. Consider reducing the dosage of rifampin as necessary and clinically appropriate, and monitor patients closely. Additive hepatotoxicity or hematologic toxicity may occur. The potential for additive adverse effects should also be considered when such medications would be prescribed after teriflunomide administration has ceased, if the patient has not received the teriflunomide elimination procedure.
Riluzole: (Moderate) Coadministration of riluzole with teriflunomide may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and teriflunomide is a CYP1A2 inducer.
Ropinirole: (Moderate) Teriflunomide is a weak inducer of CYP1A2, which may lead to decreased plasma concentrations of ropinirole, a CYP1A2 substrate. If these drugs are coadministered, adjustment of ropinirole dosage may be required.
Rosiglitazone: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as rosiglitazone. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
Rosuvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Rosuvastatin; Ezetimibe: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Rotavirus Vaccine: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exp

osure to SARS-CoV-2 virus after receiving the vaccine.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide.
Selexipag: (Major) Reduce selexipag dose to once daily when coadministered with teriflunomide due to increased exposure to the active metabolite of selexipag, which may cause side effects. Selexipag is a substrate of CYP2C8 and teriflunomide is a moderate CYP2C8 inhibitor.
Simvastatin: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Smallpox Vaccine, Vaccinia Vaccine: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and teriflunomide. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and teriflunomide is an OATP1B3 inhibitor.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with teriflunomide. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the Breast Cancer Resistance Protein (BCRP); teriflunomide is an inhibitor of BCRP. Teriflunomide is also an inhibitor of the hepatic enzyme CYP2C8. Velpatasvir is a CYP2C8 substrate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir and teriflunomide. Taking these medications together may increase voxilaprevir plasma concentrations, potentially increasing the risk for adverse events. Voxilaprevir is a substrate for the drug transporter Organic Anion Transporting Polypeptides 1B1/1B3 (OATP1B1/1B3). Teriflunomide is an OATP1B1/1B3 inhibitor. (Moderate) Use caution when administering velpatasvir with teriflunomide. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the Breast Cancer Resistance Protein (BCRP); teriflunomide is an inhibitor of BCRP. Teriflunomide is also an inhibitor of the hepatic enzyme CYP2C8. Velpatasvir is a CYP2C8 substrate.
Sumatriptan; Naproxen: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as naproxen. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects, including additive hepatotoxicity.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of teriflunomide is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a BCRP substrate and teriflunomide is a BCRP inhibitor.
Terbinafine: (Moderate) Caution is advised when administering terbinafine with teriflunomide. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP1A2 and CYP2C8; teriflunomide is an inducer of CYP1A2 and an inhibitor of CYP2C8. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered.
Theophylline, Aminophylline: (Moderate) Use caution when administering teriflunomide and theophylline; aminophylline concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as theophylline; aminophylline, may decrease theophylline exposure and lead to a reduction in efficacy.
Tizanidine: (Moderate) Use caution when administering teriflunomide and tizanidine concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as tizanidine, may decrease tizanidine exposure and lead to a reduction in efficacy.
Topotecan: (Major) Avoid coadministration of teriflunomide with oral topotecan due to increased topotecan exposure; teriflunomide may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and teriflunomide is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
Tucatinib: (Moderate) Closely monitor for tucatinib-related adverse reactions if coadministration with teriflunomide is necessary due to the risk of increased tucatinib exposure. Tucatinib is a CYP2C8 substrate and teriflunomide is a moderate CYP2C8 inhibitor.
Typhoid Vaccine: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with teriflunomide. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP drug transporter; teriflunomide is a BCRP inhibitor.
Varicella-Zoster Virus Vaccine, Live: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with teriflunomide is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP1A2 substrate and teriflunomide is CYP1A2 inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. Teriflunomide may decrease peak INR by approximately 25%. The mechanism is uncertain but, during pharmacokinetic studies, teriflunomide did not affect the pharmacokinetics of S-warfarin (a CYP2C9 substrate).
Yellow Fever Vaccine, Live: (Major) Due to the lack of clinical information related to the safety and efficacy of vaccine administration during teriflunomide use, concomitant vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of a live vaccine after stopping the medication if the teriflunomide drug elimination procedure has not been performed.
Zavegepant: (Major) Avoid concomitant use of zavegepant and teriflunomide. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and teriflunomide is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Zidovudine, ZDV: (Major) Zidovudine, ZDV should be used cautiously with other drugs that can cause bone marrow suppression including teriflunomide because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage or discontinuation of zidovudine may be warranted. Teriflunomide, an organic anion transporter OAT3 renal updake inhibitor, may cause elevated concentrations of zidovudine, an OAT3 substrate.

How Supplied

AUBAGIO/Teriflunomide Oral Tab: 7mg, 14mg

Maximum Dosage
Adults

14 mg/day PO.

Geriatric

14 mg/day PO.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Mechanism Of Action

Teriflunomide is a selective, non-competitive, and reversible inhibitor of dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. This inhibition results in antiproliferative effects among peripheral T-and B-lymphocytes, leading to a reduced concentration of activated lymphocytes in the CNS. A lower concentration of activated lymphocytes may reduce the inflammatory demyelination that occurs in multiple sclerosis. Reduced phospholipid synthesis and protein glycosylation in immune cells may also take place due to lower pyrimidine availability, which can prevent lipid messenger generation and impair the function of immune cell surface molecules.

Pharmacokinetics

Teriflunomide is administered orally and is widely distributed in plasma with protein binding greater than 99%. Approximately 3 months of use must occur before steady-state concentrations are achieved. Teriflunomide undergoes primary hydrolysis and oxidation to form minor metabolites; however, teriflunomide itself is the principal active moiety found in plasma. Secondary pathways of metabolism include oxidation, N-acetylation, and sulfate conjugation. Teriflunomide is excreted unchanged through biliary excretion and its metabolites are excreted renally. Approximately 60.1% of a dose is recovered in the feces (37.5%) or urine (22.6%) over 3 weeks; following an accelerated elimination procedure using cholestyramine, an additional 23.1% can be recovered (mostly in feces). The median half-life in healthy patients following repeated doses of 7 mg or 14 mg is approximately 18 and 19 days, respectively. Total body clearance of teriflunomide is 30.5 mL/hour following a single IV dose.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2C8, CYP1A2, and OAT3; BCRP and OATP1B1/1B3
Teriflunomide is an inhibitor of CYP2C8 in vivo, and may increase the concentrations and exposures of known CYP2C8 substrates. Teriflunomide may also be a weak inducer of CYP1A2 in vivo, and the exposure of drugs metabolized by CYP1A2 may be reduced. Teriflunomide inhibits the activity of the drug transporter OAT3 in vivo and may increase the exposure of drugs which are OAT3 substrates. Monitor these patients and adjust the dose of the concomitant drug(s) which are substrates for these enzymes or OAT3 as required. Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. Consider reducing the dose of drugs that are substrates of these drug transporters and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking teriflunomide.

Oral Route

Maximum concentrations of teriflunomide are attained within 1 to 4 hours following oral administration. After repeated doses of 7 mg or 14 mg, the AUC accumulation ratio is approximately 30. Food has no clinically relevant effect on teriflunomide oral absorption.

Pregnancy And Lactation
Pregnancy

Teriflunomide is contraindicated for use during pregnancy. Animal studies indicate that teriflunomide may cause major birth defects and/or intrauterine fetal death during human pregnancy. Prospectively collected human data (from pregnancy registries, clinical trials, pharmacovigilance cases, and published literature) of more than 150 pregnancies exposed to teriflunomide and more than 300 pregnancies exposed to leflunomide do not indicate increased birth defects or miscarriage with inadvertent teriflunomide exposure in the early first trimester followed by an accelerated elimination procedure; however, data are too limited to be conclusive. There are no data about exposures later in the first trimester and beyond. In animal reproduction studies, high incidences of fetal malformations (primarily craniofacial, and axial and appendicular skeletal defects) and embryolethality were reported at plasma exposures (AUC) lower than that at the maximum human recommended dose of 14 mg/day. No well-controlled trials in humans are available. Women who wish to become pregnant should discontinue teriflunomide and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL); the patient should use effective contraception until it is verified that the plasma concentration has been lowered to this level. Human plasma concentrations of teriflunomide less than 0.02 mg/L are expected to have minimal risk to the fetus. The patient should be counseled to immediately contact their health care provider if pregnancy is suspected (e.g., a delay in menses) during treatment or anytime within the 2 years after discontinuing the drug, since teriflunomide may stay in the blood for up to 2 years following the last dose. Perform a pregnancy test if pregnancy is suspected. An accelerated teriflunomide elimination procedure should be used to rapidly lower teriflunomide concentration, which may decrease risk to the fetus. Refer the patient to an obstetrician or gynecologist, preferably experienced in reproductive toxicity, for further evaluation and management. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to terflunomide; information about the registry can be obtained at mothertobaby.org/ongoing-study/aubagio or by calling 1-800-745-4447, option 2 or 1-877-311-8972.[51794] [61642]